A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP.
Pannexin 1 forms a large membrane channel that, based on its biophysical properties and its expression pattern, is a prime candidate to represent an ATP release channel. Pannexin 1 channel activity is potentially deleterious for cells as indicated by its involvement in the P2X7 death complex. Here we describe a negative feedback loop controlling pannexin 1 channel activity. ATP, permeant to pannexin 1 channels, was found to inhibit its permeation pathway when applied extracellularly to oocytes expressing pannexin 1 exogenously. ATP analogues, including benzoylbenzoyl-ATP, suramin, and brilliant blue G were even more effective inhibitors of pannexin 1 currents than ATP. These compounds also attenuated the uptake of dyes by erythrocytes, which express pannexin 1. The rank order of the compounds in attenuation of pannexin 1 currents was similar to their binding affinities to the P2X7 receptor, except that receptor agonists and antagonists both were inhibitory to the channel. Mutational analysis identified R75 in pannexin 1 to be critical for ATP inhibition of pannexin 1 currents.
Qiu
Feng
F
Dept. of Physiology and Biophysics, Univ. of Miami School of Medicine, PO Box 016430, Miami, FL 33101, USA.
Dahl
Gerhard
G
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000409:Alanine; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological; D008564:Membrane Potentials; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology; D014981:Xenopus
D017630:Connexins; D009419:Nerve Tissue Proteins; C546469:P2rx7 protein, mouse; C503631:Panx1 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; C082917:GJA3 protein, human; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D013498:Suramin; D000255:Adenosine Triphosphate; C004692:coomassie Brilliant Blue; D000409:Alanine